The present invention relates to a novel class of 4-aryl-1-(indanmethyl, dihydrobenzofuranmethyl or dihydrobenzothiophenemethyl)piperidine, -tetrahydropyridine or -piperazine compounds having effects at central serotonergic receptors. These methylamine compounds are therefore useful in the treatment of certain psychic and neurologic disorders.
A few aminomethylindan, -dihydrobenzofurane and -dihydrobenzothiophene compounds are known from the prior art.
So, EP patent 0 281 261 discloses 1-aminomethylindan, 3-aminomethylbenzofurane and 3-aminomthylbenzothiophene derivatives with a hydroxy group or a substituted hydroxy group in the 6-position (indan) or 5-position (benzofurane, benzothiophene). These compounds were found to show central dopamine agonist activity, in particular to show effect at presynaptic dopamine receptors.
In U.S. Pat. No. 4,500,543 certain 1-aminomethylphtalane compounds are said to show adrenergic effects and, accordingly, antihypertensive and heart rate decreasing properties. Said patent generically covers compounds having substituents in the 5-, 6- and/or 7-position.
EP 0325963 A1 discloses among other compounds a class of 1-aminomethyl indan compounds in which the aminomethyl group may constitute a 1-pyrrolylmethyl group which is substituted with thienyl or phenyl. The compounds are claimed to be xcex12 antagonists useful in the treatment of depression, metabolic disorders, glaucoma, migraine and hypertension.
Furthermore, EP 0490772 A1 describes i.a. a class of 4-benzofuranyl- or 4-benzodioxanyl-1-indanylmethyl piperazine compounds being 5-HT1A ligands.
EP 0428437 generically covers a very broad class of 1,2-benzoisoxazole compounds including certain 3-[1-[(1-indanyl)methyl]-1,2-benzoisoxazoles. However, only one such compound is examplified and in that case without giving any data. The compounds are said to show dopamine and serotonin antagonistic activities.
U.S. Pat. No. 3,886,168 relates to 1-[(indan-1-yl)methyl]piperidine compounds having antihypertensive activity.
Various effects are known with respect to compounds which are ligands at the different serotonin receptor subtypes. As regards the 5-HT2A receptor, which was previously referred to as the 5-HT2 receptor, the following effects have e.g. been reported:
The 5-HT2A antagonist ritanserin (Meert, T. F.; Janssen, P. A. J. Drug. Dev. Res. 1989, 18, 119.) has been shown to be effective in the treatment of anxiety and depression presumably through improvement of the sleep quality. Furthermore, selective, centrally acting 5-HT2A antagonists have been shown to have an effect towards the negative symptoms of schizophrenia and to reduce extrapyramidal side-effects caused by treatment with classical neuroleptics in schizophrenic patients (Gelders, Y. G., British J. Psychiatry, 1989, 155 (suppl.5), 33). Finally, selective 5-HT2A antagonists could be effective in the prophylaxis and treatment of migraine since it is known that 5-HT is involved in migraine attacks. The links between 5-HT and migraine attacks are several and they suggest a number of mechanisms whereby 5-HT may be involved (Scrip Report; xe2x80x9cMigrainexe2x80x94Current trends in research and treatmentxe2x80x9d; PJB Publications Ltd.; May 1991).
The serotonin 5-HT2A antagonist, MDL 100,907 (Sorensen, S. M. et al., J. Pharmacol. Exp. Ther. 1993, 266, 684-691), and certain compounds within series of 1-phenyl-indoles (WO 93/12790) and 3-phenylindole derivatives (WO 93/14758) have shown anti-psychotic activity in animal models with indication of no liability of no liability to cause extrapyramidal side effects (EPS).
Clinical studies of known 5-HT1A partial agonists such as e.g. buspirone, 8-[4-[4-(2-pyrimidyl)-1-piperazinyl]butyl]-8-azaspiro[4,5]decane-7,9-dione, gepirone, 4,4-dimethyl-1-[4-[4-(2-pyrimidyl)-1-piperazinyl]butyl]-2,6-piperidinedione, and ipsapirone, 2-[4-[4-(2-pyrimidyl)-1-piperazinyl]butyl]-1,2-benzothiazol-3(2H)-one-1,1-dioxide, have shown that 5-HT1A partial agonists are useful in the treatment of anxiety disorders such as generalised anxiety disorder, panic disorder, and obsessive compulsive disorder (Glitz, D. A., Pohl, R., Drugs 1991, 41, 11). Preclinical studies indicate that also full agonists are useful in the treatment of the above mentioned anxiety related disorders (Schipper, Human Psychopharmacol., 1991, 6, S53).
There is also evidence, both clinical and preclinical, in support of the beneficial effect of 5-HT1A partial agonists in the treatment of depression, impulse control disorders and alcohol abuse (van Hest, Psychopharmacol., 1992, 107, 474; Schipper et al, Human Psychopharmacol., 1991, 6, S53; Cervo et al, Eur. J. Pharm., 1988, 158, 53; Glitz and Poh, Drugs 1991, 41, 11; Grof et al., Int. Clin. Psychopharmacol. 1993, 8, 167-172; Ansseau et al., Human Psychopharmacol. 1993, 8, 279-283).
5-HT1A agonists and partial agonists inhibit isolation-induced aggression in male mice indicating that these compounds are useful in the treatment of aggression (Sanchxc3xa9z et al., Psychopharmacology, 1993, 110, 53-59).
Furthermore, 5-HT1A ligands have been reported to show antipsychotic effect in animal models (Wadenberg and Ahlenius, J. Neural. Transm., 1991, 83, 43; Ahlenius, Pharmacol.andToxicol., 1989, 64, 3; Lowe et al., J. Med. Chem., 1991, 34, 1860; New et al., J. Med. Chem., 1989, 32, 1147; and Martin et al., J. Med. Chem., 1989, 32, 1052).
Recent studies also indicate that 5-HT1A receptors are important in the serotonergic modulation of haloperidol-induced catalepsy (Hicks, Life Science 1990, 47, 1609, Wadenberg et al. Pharmacol.Biochem. and Behav. 1994, 47, 509-513) suggesting that 5-HT1A agonists are useful in the treatment of EPS induced by conventional antipsychotic agents such as haloperidol.
5-HT1A agonists have shown neuroprotective properties in rodent models of focal and global cerebral ischaemia and may, therefore, be useful in the treatment of ischaemic disease states (Prehn, Eur. J. Pharm. 1991, 203, 213).
Pharmacological studies have been presented which indicates that 5-HT1A antagonists are useful in the treatment of senile dementia (Bowen et al, Trends Neur. Sci. 1992, 15, 84).
Both in animal models and in clinical trials it has been shown that 5-HT1A agonists exert antihypertensive effects via a central mechanism (Saxena and Villalxc3x3n, Trends Pharm. Sci. 1990, 11, 95; Gillis et al, J. Pharm. Exp. Ther. 1989, 248, 851). 5-HT1A ligands may, therefore, be beneficial in the treatment of cardiovascular disorders.
5-HT reuptake inhibitors are well known antidepressant drugs.
As 5-HT1A and 5-HT2A receptor ligand classes of compounds and 5-HT reuptake inhibitors have different activities in different animal models predictive of anxiolytic and antiaggressive effects (Perregaard et al., Recent Developments in Anxiolytic. Current Opinion in Therapeutic Patents 1993, 1, 101-128) and/or in models predictive of effects in other psychic disorders it might also be highly beneficial to treat complex states of anxiety, depression, or other psychic disorders with a drug which have combined serotonergic effects.
It has now been found that certain novel 4-aryl-1-(indanmethyl, dihydrobenzofuranmethyl or dihydrobenzothiophenemethyl)piperidines, -tetrahydropyridines or -piperazines interact potently with central serotonergic receptors, in particular with the 5-HT1A and/or the 5-HT2A receptors.
Accordingly, the present invention relates to novel compounds of the formula I. 
wherein one of X and Y is CH2 and the other one is selected from the group consisting of CH2, O, and S;
the dotted line, emanating from Z, indicates an optical bond; when it does not indicate a bond Z is N, CH or COH; and when it indicates a bond Z is C;
Ar is phenyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-pyrimidyl, 1-indolyl, 2-indolyl, 3-indolyl, 1-indol-2-onyl, 3-indol-2-onyl, 2- or 3-benzofuranyl, 2- or 3-benzothiophenyl, 1-naphthyl or 2-naphthyl, each optionally substituted with halogen, lower alkyl, lower alkoxy, lower alkylthio, hydroxy, lower alkylsulfonyl, cyano, trifluoromethyl, trifluromethylsulfonyloxy, cycloalkyl, cycloalkyl-lower-alkyl, nitro, amino, lower alkylamino, di-lower alkylamino, acylamino or C1-2 alkylenedioxy;
R1 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalk(en)yl, cycloalk(en)-yl-lower alk(en/yn)yl, aryl, aryl-lower alkyl, acyl, thioacyl, lower alkylsulfonyl, trifluoromethylsulfonyl, arylsulfonyl,
R1 is a group R9VCOxe2x80x94 where V is O or S and R9 is lower alkyl, cycloalkyl, cycloalkyl-lower-alkyl or aryl, or
R1 is a group R10R11NCOxe2x80x94 or R10R11NCSxe2x80x94 wherein R10 and R11 are independently hydrogen, lower alkyl, cycloalkyl, cycloalkyl-lower-alkyl or aryl, or R10 and R11 together with the N-atom to which they are linked, form a pyrrolidinyl, piperidinyl or perhydroazepin group;
R2 is hydrogen, lower alkyl, cycloalkyl or cycloalkyl-lower-alkyl;
or R1 and R2 together with the N-atom to which they are linked form a group, 
xe2x80x83wherein Q is Cxe2x95x90O, Cxe2x95x90S or CH2; T is NH, S, O or CH2; and m is 1-4, inclusive;
R3-R5 are independently hydrogen, halogen, lower alkyl, lower alkylcarbonyl, phenylcarbonyl, halogen substituted phenylcarbonyl, lower alkoxy, lower alkylthio, hydroxy, lower alkylsulfonyl, cyano, trifluoromethyl, cycloalkyl, cycloalkyl-lower-alkyl or nitro;
R6 and R7 are each hydrogen or lower alkyl or they are linked together to constitute a 3-7-membered carbocyclic ring;
R8 is hydrogen or lower alkyl;
any alkyl, cycloalkyl or cycloalkylalkyl group present being optionally substituted with one or two hydroxy groups, which again are optionally esterified with an aliphatic or aromatic carboxylic acid; and any aryl substituent present being optionally substituted with halogen, lower alkyl, lower alkoxy, lower alkylthio, hydroxy, lower alkylsulfonyl, cyano, trifluoromethyl, trifluoromethylsulfonyloxy, cycloalkyl, cycloalkyl-lower-alkyl or nitro;
and pharmaceutically acceptable acid addition salts thereof.
The compounds of the invention have been found to show potent affinity to 5-HT1A receptors and/or to 5-HT2A receptors. In addition to the effect at these receptor subtypes, certain of the present compounds also show 5-HT reuptake inhibiting effect.
Accordingly, the compounds of the invention are considered useful in the treatment of positive and negative symptoms of schizophrenia, other psychoses, anxiety disorders, such as generalised anxiety disorder, panic disorder, and obsessive compulsive disorder, depression, alcohol abuse, impulse control disorders, aggression, side effects induced by conventional antipsychotic agents, ischaemic disease states, migraine, senile dementia and cardiovascular disorders and in the improvement of sleep.
In another aspect the invention provides a pharmaceutical composition comprising at least one compound of Formula I as defined above or a pharmaceutically acceptable acid addition salt thereof or prodrug thereof in a therapeutically effective amount and in combination with one or more pharmaceutically acceptable carriers or diluents.
In a further aspect the present invention provides the use of a compound of Formula I as defined above or an acid addition salt or prodrug thereof for the manufacture of a pharmaceutical preparation for the treatment of the above mentioned disorders.
Compounds of general Formula I exist as optical isomers thereof and such optical isomers are also embraced by the invention.
Prodrugs of the compounds of general Formula I are also embraced by the invention.
The term cycloalkyl designates a carbocyclic ring having 3-8 carbon atoms, inclusive, or a bicyclic or tricyclic carbocycle, such as adamantyl.
The term lower alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl and 2-methyl-1-propyl. The terms lower alkoxy, lower alkylthio, lower alkylsulfonyl, lower alkylamino, lower alkylcarbonyl, etc. designate such groups in which the alkyl group is lower alkyl as defined above. Similarly, lower alkenyl and alkynyl, respectively, designate such groups having from two to six carbon atoms, inclusive. Preferred groups are those having up to four carbon atoms.
The term aryl refers to a mono- or bicyclic carbocyclic or heterocyclic aromatic group, such as phenyl, indolyl, thienyl, pyrimidyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzofuranyl, benzothienyl, pyridyl, naphthyl and furanyl, in particular phenyl, pyrimidyl, indolyl, and thienyl.
Halogen means fluoro, chloro, bromo or iodo.
As used herein the term acyl refers to a formyl, lower alk(en/yn)ylcarbonyl, arylcarbonyl, aryl-lower alk(en/yn)ylcarbonyl, cycloalkylcarbonyl, or cycloalkyl-lower-alk(en/yn)ylcarbonyl group.
The term thioacyl is the corresponding acyl group in which the carbonyl group is replaced with a thiocarbonyl group.
The expression alk(en/yn)yl means that the group may be an alkyl, alkenyl, or alkynyl group.
In Formula I, X is preferably CH2 or S and Y is preferably CH2 and most preferably they are both CH2.
R1 is preferably acyl, lower alkyl, lower alkoxy, a group R10R11NCOxe2x80x94 or R10R11NCSxe2x80x94 wherein R10 is hydrogen, lower alkyl, cycloalkyl, cycloalkyl-lower-alkyl or aryl and R11 is hydrogen or lower alkyl or R10 and R11 together with the N-atom to which they are linked, form a pyrrolidinyl, piperidinyl or perhydroazepin group. Most preferably, R1 is formyl, acetyl, methylaminocarbonyl, methylaminothiocarbonyl, dimethylaminocarbonyl, dimethylaminothiocarbonyl, methylsulfonyl, aminocarbonyl, cyclopropylcarbonyl, methyl, pyrrolidinylcarbonyl or 4-fluorophenylaminocarbonyl. R2 is preferably hydrogen or lower alkyl, most preferably hydrogen or methyl, or R1 and R2 are linked together to form a 5-7 membered unsubstituted lactam ring or a pyrrolidinyl, piperidinyl or perhydroazepin.
R3-R5 are preferably hydrogen, fluoro, chloro, bromo, methyl, trifluoromethyl or acetyl and R6-R8 are preferably all hydrogen.
Finally, Ar is preferably phenyl, 3-indolyl, 1-indolyl, or pyrimidyl or phenyl, 3-indolyl, 1-indolyl or pyrimidyl substituted with halogen.
A preferred subclass of compounds are those wherein R1 is acetyl and R2 is H and in particular such compounds wherein Ar is indolyl or phenyl substituted with halogen, especially chloro. If Ar is 3-indolyl it is preferably substituted in the 6-position and if it is phenyl, it is preferably substituted in the 4-position.
Another preferred subclass of compounds of the invention are those wherein R1 is a group R10R11NCOxe2x80x94 or R10R11NCSxe2x80x94 wherein R10 is hydrogen, lower alkyl, cycloalkyl, cycloalkyl-lower-alkyl or aryl and R11 is hydrogen or lower alkyl and R2 is hydrogen.
In a further preferred subclass of compounds R1 is hydrogen, lower alkyl or lower alkylsulfonyl in particular methyl or methylsulfonyl and R2 is hydrogen or lower alkyl, in particular methyl, or R1 and R2 are linked together to form a pyrrolidinon ring or a pyrrolidinyl ring.
Preferred compounds are:
1-(6-Acetylaminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.
(+)-1-(6-Acetylaminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.
(xe2x88x92)-1-(6-Acetylaminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine
1-(6-Acetylamino-5-fluoroindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.
1-(6-Acetylamino-4-fluoroindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.
1-(6-Acetylamino-4-bromoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.
1-(6-Acetylamino-4-nitroindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.
1-(6-Acetylamino-4-cyanoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.
1-(6-Acetylamino-5-chloroindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.
1-(6-Acetylamino-5-bromoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.
1-(6-Acetylamino-5-cyanoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.
1-(6-Acetylamino-7-chloroindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.
1-(6-Acetylamino-7-fluoroindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.
1-(5-Acetyl-6-acetylaminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.
1-(6-Acetylamino-1-methylindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.
1-(6-Acetylaminoindan-1-ylmethyl)-4-(3-fluorophenyl)piperidine.
1-(6-Acetylaminoindan-1-ylmethyl)-4-(2-fluorophenyl)piperidine.
1-(6-Acetylaminoindan-1-ylmethyl)-4-(4-methylphenyl)piperidine.
1-(6-Acetylaminoindan-1-ylmethyl)-4-(4-dimethylaminophenyl)piperidine.
1-(6-Acetylaminoindan-1-ylmethyl)-4-(4-aminophenyl)piperidine.
1-(6-Acetylaminoindan-1-ylmethyl)-4-(3-trifluoromethylphenyl)piperidine.
1-(6-Acetylaminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.
1-(5-Acetylamino-2,3-dihydrobenzothiophen-3-ylmethyl)-4-(4-fluorophenyl)piperidine.
1-(6-Acetylamino-1,3-dihydroisobenzofuran-1-ylmethyl)-4-(4-fluorophenyl)piperidine.
1-(6-Acetylaminoindan-1-ylmethyl)-4-(4-chlorophenyl)piperazine.
1-(6-Acetylaminoindan-1-ylmethyl)-4-(3-chlorophenyl)piperazine.
1-(6-Acetylaminoindan-1-ylmethyl)-4-(2-chlorophenyl)piperazine.
1-(6-Acetylaminoindan-1-ylmethyl)-4-(4-trifluoromethylsulfonyloxyphenyl)piperazine.
1-(6-Acetylaminoindan-1-ylmethyl)-4-(3,4-dichlorophenyl)piperazine.
1-(6-Acetylaminoindan-1-ylmethyl)-4-(3,4-dichlorophenyl)piperidine.
1-(6-Acetylaminoindan-1-ylmethyl)-4-(2-methoxyphenyl)piperazine.
1-(6-Acetylaminoindan-1-ylmethyl)-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine.
1-(6-Acetylaminoindan-1-ylmethyl)-4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine.
1-(6-Acetylaminoindan-1-ylmethyl)-4-(2-pyrimidyl)piperidine.
1-(6-Acetylaminoindan-1-ylmethyl)-4-(2-pyrimidyl)piperazine.
1-(6-Acetylaminoindan-1-ylmethyl)-4-(2-pyridinyl)piperazine.
1-(6-Acetylaminoindan-1-ylmethyl)-4-(3-thienyl)piperidine.
1-(6-Acetylaminoindan-1-ylmethyl)-4-(2-thienyl)piperidine.
1-(6-Acetylaminoindan-1-ylmethyl)-4-(3-thienyl)piperazine.
1-(6-Acetylaminoindan-1-ylmethyl)-4-(1-naphthyl)piperidine.
1-(6-Acetylaminoindan-1-ylmethyl)-4-(2-naphthyl)piperidine.
1-(6-butanoylaminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine
1-(6-Formylaminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.
1-(6-Formylaminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperazine.
4-(4-Fluorophenyl)-1-(6-methansulfonylaminoindan-1-ylmethyl)piperidine.
1-(6-Cyclopropylcarbonylaminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.
1-(6-Cyclopentylcarbonylaminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.
4-(4-Fluorophenyl)-1-(6-methylaminocarbonylaminoindan-1-ylmethyl)piperidine.
1-[6-(4-Fluorophenyl)aminocarbonylaminoindan-1-ylmethyl]-4-(4-fluorophenyl)piperidine.
4-(4-Fluorophenyl)-1-(6-methylaminothiocarbonylaminoindan-1-ylmethyl)piperidine.
1-(6-Dimethylaminocarbonylaminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.
1-(6-Dimethylaminothiocarbonylaminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.
4-(4-Fluorophenyl)-1-[6-(1-pyrrolidinyl)carbonylaminoindan-1-ylmethyl]piperidine.
1-(6-Aminocarbonylaminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.
1-(6-Ethoxycarbonylaminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.
1-[6-(N,N-dimethylamino)indan-1-ylmethyl]-4-(4-fluorophenyl)piperidine.
3-[1-(5-Acetylamino-2,3-dihydrobenzothiophen-3-ylmethyl)piperidin-4-yl]-5-chloro-1H-indole.
3-[1-(5-Acetylamino-2,3-dihydrobenzothiophen-3-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-5-chloro-1H-indole.
3-[1-(6-Acetylaminoindan-1-ylmethyl)piperidin-4-yl]-5-fluoro-1H-indole.
3-[1-(6-Acetylamino-2,3-dihydrobenzothiophen-3-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-5-fluoro-1H-indole.
3-[1-(6-Acetylaminoindan-1-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole.
3-[1-(6-Acetylaminoindan-1-ylmethyl)piperidin-4-yl]-6-chloro-1H-indole.
3-[1-(6-Acetylaminoindan-1-ylmethyl)piperidin-4-yl]-6-chloro-1-methyl-1H-indole.
1-[1-(6-Acetylaminoindan-1-ylmethyl)piperidin-4-yl]-6-chloro-1H-indole.
1-[1-(6-Acetylaminoindan-1-ylmethyl)piperidin-4-yl]-5-chloro-1H-indole.
3-[1-(6-Acetylaminoindan-1-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-5-chloro-1H-indole.
4-(4-Fluorophenyl)-1-[6-(1-pyrrolidin-2-onyl)indan-1-ylmethyl]piperidine.
4-(4-Fluorophenyl)-1-[6-(1-piperidin-2-onyl)indan-1-ylmethyl]piperidine.
1-[6-(4-Fluorophenylamino)indan-1-ylmethyl]-4-(4-fluorophenyl)piperidine
3-[1-(6-Acetylaminoindan-1-ylmethyl)piperidin-4-yl]-6-chlorobenzothiophene.
3-[1-(6-Acetylaminoindan-1-ylmethyl)-1,2,3,6-tetrahydropyridin4-yl]-6-chlorobenzothiophene.
3-[1-(6-Acetylaminoindan-1-ylmethyl)piperidin-4-yl]-5-chlorobenzothiophene.
2-[1-(6-Acetylaminoindan-1-ylmethyl)piperidin-4-yl]-6-chlorobenzothiophene.
3-[1-(6-Acetylaminoindan-1-ylmethyl)piperidin-4-yl]-6-chlorobenzofurane.
3-[1-(6-Acetylaminoindan-1-ylmethyl)piperidin-4-yl]-6-chloro-1H-indol-2-one
3-[1-(6-Acetylaminoindan-1-ylmethyl)piperidin-4-yl]-6-chloro-1-methyl-1H-indol-2-one.
3-[1-(6-Acetylaminoindan-1-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1-methyl-1H-indol-2-one.
2-[1-(6-Acetylaminoindan-1-ylmethyl)piperidin-4-yl]-6-chloro-1H-indole.
1-[1-(6-Acetylaminoindan-1-ylmethyl)piperidin-4-yl]-5-chloro-1H-indol-2-one.
3-[1-(6-Methylaminokarbonylaminoindan-1-ylmethyl)piperidin-4-yl]-5-chloro-1H-indole.
3-[1-(6-Methylaminokarbonylaminoindan-1-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole.
1-(6-Acetylaminoindan-1-ylmethyl)-4-(4-bromophenyl)piperidine.
1-(6-Acetylaminoindan-1-ylmethyl)-4-hydroxy-4-(4-chlorophenyl)piperidine.
1-(6-Acetylaminoindan-1-ylmethyl)-4-(3-trifluoromethyl-4-chlorophenyl)piperazine.
1-(6-Acetylaminoindan-1-ylmethyl)-4-(2-chloro-3-thienyl)piperazine.
1-(6-Acetylaminoindan-1-ylmethyl)-4-(4-chloro-2-thienyl)piperidine.
1-(6-Acetylaminoindan-1-ylmethyl)-4-(3,4-methylendioxyphenyl)piperidine.
1-(6-Acetylaminoindan-1-ylmethyl)-4-(3,4-methylendioxyphenyl)piperazine.
1-(6-Methylaminocarbonylaminoindan-1-ylmethyl)-4-(3,4-methylendioxyphenyl)piperazine.
1-(6-Acetylaminoindan-1-ylmethyl)-4-hydroxy-4-(3-trifluoromethyl-4-chlorophenyl)piperidine.
1-(6-Acetylaminoindan-1-ylmethyl)-4-acetyloxy-4-(3-trifluoromethyl-4-chlorophenyl)piperidine.
5-chloro-1-[1-(6-methylaminocarbonylaminoindan-1-ylmethyl)piperidin-4-yl]-1H-indole
The acid addition salts of the invention are pharmaceutically acceptable salts of the compounds of Formula I formed with non-toxic acids. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, embonic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids.
The pharmaceutical compositions of this invention or those which are manufactured in accordance with this invention may be administered by any suitable route, for example orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of solutions for injection. For preparing such compositions, methods well known in the art may be used, and any pharmaceutically acceptable carriers, diluents, excipients, or other additives normally used in the art may be used.
Conveniently, the compounds of the invention are administered in unit dosage form containing said compounds in an amount of about 0.01 to 100 mg.
The total daily dose is usually in the range of about 0.05-500 mg, and most preferably about 0.1 to 50 mg of the active compound of the invention.
The invention moreover relates to a method for the preparation of the novel 4-Aryl-1-[amino(indan, dihydrobenzofuran or dihydrobenzothiophene)methyl]piperidines, -tetrahydropyridines or -piperazines of Formula I, comprising:
a) reacting an amino derivative of the following Formula II: 
xe2x80x83wherein R2-R8, X, Y, Z, Ar, and the dotted line are as previously defined, with a reagent of the formula R1xe2x80x2-hal or R1xe2x80x2-OCOR, in which formulas hal is halogen, R is alkyl, aryl or alkoxy and R1xe2x80x2 is acyl, thioacyl, a group R9VCOxe2x80x94, or a group R10R11NCOxe2x80x94 or R10R11NCSxe2x80x94 where R9, V, R10 and R11 are as previously defined except that neither R10 nor R11 may be hydrogen, or with a lower alkylsulfonyl halogenide, trifluoromethylsulhonyl halogenide or an isocyanate or thioisocyanate of the formula R10xe2x80x94Nxe2x95x90Cxe2x95x90O or R10xe2x80x94Nxe2x95x90Cxe2x95x90S wherein R10 is as previously defined;
b) in order to prepare a compound of Formula I wherein R1 is lower alk(en/yl)yl, cycloalk(en)yl, cycloalk(en)yl-lower alk(en/yn)yl or aryl-lower alkyl, alkylating an amino derivative of Formula II with an alkylating agent such as an alkylhalogenide R1-hal, a mesylate R1xe2x80x3OSO2CH3, a tosylate R1xe2x80x3OSO2C6H4xe2x80x94CH3, or a similar alkylating reagent with suitable leaving groups, R1 being lower alkyl, lower alkenyl, lower alkynyl, cycloalk(en)yl, cycloalk(en)yl-lower alk(en/yn)yl or aryl-lower alkyl;
c) reducing the tetrahydropyridinyl double bond in derivatives of the following Formula III: 
xe2x80x83wherein R1-R8, X, Y, and Ar are as previously defined; or
d) alkylating an arylpiperazine, arylpiperidine, or aryltetrahydropyridine of the formula V with an alkylating derivative of the formula IV: 
xe2x80x83wherein R1-R8, X, Y, Z, Ar, and the dotted line are as previously defined, and w is a leaving group such as eg. halogen, mesylate, or tosylate; or
e) in order to obtain to form a compound of Formula I in which the substituents R1 and R2 together constitute a ring, ringclosure of a derivative of Formula VI: 
xe2x80x83in which R3-R8, X, Y, Z, Ar, m, Q, T and the dotted line are as previously defined and w is a leaving group such as halogen, mesylate, or tosylate;
f) in order to obtain a compound of Formula I in which R1 is lower alk(en/yn)yl, cycloalk(en)yl, cycloalk(en)yl-lower alk(en/yn)yl or aryl-lower alkyl, reducing the carbonyl group of an amide derivative of the following Formula VII: 
xe2x80x83wherein R2-R8, X, Y, Z, Ar and the dotted line are as previously defined and R1xe2x80x3xe2x80x2 is such a group that the group R1xe2x80x3xe2x80x2CH2 constitutes a lower alk(en/yn)yl, cycloalk(en)yl, cycloalk(en)yl-lower alk(en/yn)yl or aryl-lower alkyl as embraced by the definition of R1; or
g) introducing a substituent R3, R4 or R5 by reacting a compound of the following Formula VIII: 
xe2x80x83wherein one of R3xe2x80x2-R5 is hydrogen and the other two are the corresponding R3, R4 or R5 as previously defined and R1, R2, R6-R8, X, Y, Z, Ar and the dotted line are as previously defined, by using a reactive reagent such as a halogen or a halogenating agent, a sulfonating agent, a nitration agent or a reactive agent generating carbonium ions (RCO+, R+) wherein R is alkyl alkynyl, aryl cycloalkyl, or cycloalk (en/yn)yl; or
h) reducing the double bond in a compound of the following Formula IX: 
xe2x80x83wherein R1-R8, X, Y, Z, and Ar are as previously defined and one of the two dotted lines indicates a double bond; or
i) reducing the amide carbonyl in a compound of the following Formula X: 
xe2x80x83wherein R1-R5, R8, X, Y, Z, Ar and the dotted line are as previously defined.
whereupon the compound of Formula I is isolated as the free base or a pharmaceutically acceptable acid addition salt thereof.
The reaction in Method a) is conveniently performed at low temperature (eg. below room temperature) in an inert solvent such as acetone, dichloromethane, tetrahydrofuran or dimethoxyethane when reactive carboxylic acid chlorides, isocyanates, or isothiocyanates are used. Formylated amines are prepared from the corresponding amines by reaction in formic acid, with esters of formic acid, or by reaction with mixed formic acid anhydride prepared in situ. Generally reaction temperatures are between 0xc2x0 C. and the boiling point of the formyl precursor compounds.
The alkylations according to Methods b) and d) are generally performed by refluxing in a suitable solvent such as acetone, methyl isobutyl ketone, tetrahydrofuran, dioxane, ethanol or 2-propanol in the presence of a base such as triethylamine or potassium carbonate.
The reductions of double bonds according to Methods c) and h) are generally performed by catalytic hydrogenation at low pressure ( less than 3 atm.) in a Parr apparatus, or by using reducing agents such as diborane in inert solvents such as tetrahydrofuran, dioxane, or diethyl ether.
The reductions according to Methods f) and i) are generally performed by use of LiAlH4, AlH3 or diborane in an inert solvent such as tetrahydrofuran, dioxane, or diethyl ether at room temperature or at a slightly elevated temperature.
The halogenation according to Method g) is generally performed by use of chlorine, bromine, or N-chlorosuccinimide, N-bromosuccinimide or another halogen precursor molecule, conveniently in the presence of a catalyst such as Fe ions or a mineral acid.
1-Unsubstituted 4-arylpiperazines of Formula V (Zxe2x95x90N) are either commercially available or may be synthesized from the corresponding anilines and Nxe2x80x2,Nxe2x80x2-bis(2-chloroethyl)amine by refluxing in high boiling solvents as chlorobenzene typically for 2-3 days according to methods described by Martin et al. J.Med.Chem. 1989, 32 1052-1056.
4-Arylpiperidines of formula V (Zxe2x95x90CH) are either commercially available or prepared as described in eg. U.S. Pat. No. 2,891,066; McElvain et al. J. Amer. Chem. Soc. 1950, 72, 3134; Bally et al Chem.Ber. 1887, 20, 2590. The corresponding 4-aryl-1,2,3,6-tetrahydropyridines of Formula V (Zxe2x95x90C) are prepared from N-protected 4-piperidones by addition of properly substituted aryl lithium or magnesium halides followed by acid catalyzed water elimination. The N-protecting group (carbamate, benzyl, sulfonyl, acetyl) is finally removed in a conventional manner.
Synthesis of 3-(4-piperidinyl)-1H-indoles and 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles is described in the Experimental Section.
Key intermediates such as 1-indancarboxylic acid (V. Asham and W. H. Linnell, J. Chem. Soc. 1954, 4691-4693, Hansen et al. Helv.Chim.Acta 1982, 33, 325-343), and 5-nitro-3-benzothiophenecarboxylic acid (EP Pat. Appln. No. 88-301073 CA(110(9):75302y (1988) and references cited therein) were prepared according to well-known literature procedures.
In the following the invention is further illustrated examples which, however, may not be construed as limiting.
In all the Examples, melting points were determined on a Bxc3xcchi SMP-20 apparatus. Melting points are given as uncorrected values. 1H NMR spectra were recorded at 250 MHz on a Bruker AC 250 spectrometer. Deuterated chloroform (99.8%D) or dimethylsulfoxide (99.9%D) were used as solvents. TMS was used as internal reference standard. Chemical shift values are expressed in ppm-values. The following abbreviations are used for multiplicity of NMR signals: s=singlet, d=doublet, t=triplet, q=quartet, qui=quintet, h=heptet, dd=double doublet, dt=double triplet, dq=double quartet, tt=triplet of triplets, m=multiplet.